ABSTRACT
Mouse models are useful for the early down-selection of malaria vaccine candidates. The Walter Reed Army Institute of Research has optimized a transgenic Plasmodium berghei sporozoite challenge model to compare the efficacy of Plasmodium falciparum circumsporozoite protein (CSP) vaccines. GSK's RTS,S vaccine formulated in the adjuvant AS01 can protect malaria-naïve individuals against malaria. We report that the RTS,S/AS01 vaccine induces high level sterile protection in our mouse model. Down titration of the antigen at a constant AS01 dose revealed a potent antigen dose-sparing effect and the superiority of RTS,S/AS01 over a soluble CSP antigen. RTS,S-mediated protective immunity was associated with a threshold of major repeat antibody titer. Combined titration of the antigen and adjuvant showed that reducing the adjuvant could improve antibody boosting post-3rd vaccination and reduce the threshold antibody concentration required for protection. Mouse models can provide a pathway for preclinical assessment of strategies to improve CSP vaccines against malaria.
ABSTRACT
BACKGROUND: Indian-origin rhesus (InR) are preferred for research, but strict export restrictions continue to limit their use. Chinese-origin rhesus (ChR), although easier to procure, are genetically distinct from InR and differ in their immune response to infectious agents, such as the Simian Immunodeficiency Virus. The most advanced malaria vaccine, RTS,S (GlaxoSmithKline), is based on the circumsporozoite protein (CSP) of Plasmodium falciparum. The efficacy of RTS,S vaccine in the field remains low and short-lived; efforts are underway to improve CSP-based vaccines. Rhesus models can accelerate preclinical down-selection of the next generation of malaria vaccines. This study was used to determine if the safety and immunogenicity outcomes following vaccination with a CSP vaccine would differ in the InR and ChR models, given the genetic differences between the two sub-populations of rhesus. METHODS: The FMP013 vaccine, was composed of nearly full-length soluble P. falciparum CSP produced in Escherichia coli and was adjuvanted with the Army liposomal formulation (ALFQ). Three doses of the vaccine were administered in InR and ChR (n = 6) at 1-month intervals and the antibody and T cell responses were assessed. RESULTS: Local and systemic toxicity profile of FMP013 vaccine in InR and ChR were similar and they revealed that the FMP013 vaccine was safe and caused only mild and transient inflammatory adverse reactions. Following the first 2 vaccines, there was a slower acquisition of antibodies to the CSP repeat region in ChR. However after the 3rd vaccination the titers in the two models were comparable. The ChR group repeat-specific antibodies had higher avidity and ChR group showed higher inhibition of liver stage development activity compared to InR. There was no difference in T-cell responses to the FMP013 vaccine between the two models. CONCLUSIONS: A difference in the quality of serological responses was detected between the two sub-populations of rhesus. However, both models confirmed that FMP013/ALFQ vaccine was safe, highly immunogenic, elicited functional antibodies and T-cell responses. Overall, the data suggests that rhesus of Indian and Chinese origins can be interchangeably used to compare the safety and immunogenicity of next-generation of malaria vaccines and adjuvants.
